ABSTRACT Esophageal cancer, especially squamous cell cancer (ESCC) and adenocarcinoma (EAC), carries a dismal prognosis as the preponderance of patients present at late stages, thereby defying traditional chemoradiation therapy. Advances in molecular pathogenesis and therapy will provide a foundation for therapy of squamous cell cancers and adenocarcinomas at other sites (e.g. head and neck, as well as lung). This is a competing renewal of the NCI P01entitled Mechanisms of Esophageal Carcinogenesis that has made substantial significant and impactful progress in elucidating the molecular mechanisms underlying esophageal carcinogenesis with translation to new strategies in therapy. Novel, innovative models have been generated involving 3D organotypic cultures, in vivo bioluminescence imaging in immunodeficient mice and genetically engineered mice that permit recapitulation, for the first time, cardinal genetic features of esophageal squamous cell cancer and esophageal adenocarcinoma. New insights have been gained into the esophageal tumor microenvironment, revealing that the interplay between transformed esophageal epithelial cells, cancer associated fibroblasts (CAFs), immature myeloid cells (myeloid derived suppressor cells (MDSCs), and endothelial cells are critical in fostering tumorigenesis. Mechanisms have been identified that underlie resistance to chemoradiation therapy. The experience and expertise of the Project Leaders, in concert with the platforms provided by the Core Facilities, will result in enhancement of the research that would not be possible if the projects were independent of each other. Project 1 (Rustgi, Project Leader) will focus upon the biological roles of the cooperation between p120-catenin and p53 tumor suppressor genes in the formation of esophageal tumor cells as well as the interplay of these tumor cells with CAFs and MDSCs in the esophageal tumor microenvironment. Project 2 (Diehl, Project Leader) elucidates the manner in which cyclin D1 is regulated and defines the novel role of the Fbx4 mutations in esophageal carcinogenesis, with translation into the development of therapeutic approaches. Specifically, SCFFBX4-aB crystallin E3 ligase maintains threshold levels of the cyclin D1/CDK4 kinase critical for esophageal cell growth and homeostasis. Therapeutic strategies targeting the cyclin D1/CDK4 kinase, or key downstream effectors (such as PRMT5) may provide significant therapeutic benefit in the treatment of esophageal cancer. Project 3 (K-K Wong, Project Leader) has discovered genomic amplifications of genes encoding ERBB-family kinases and cell cycle mediators in esophageal cancers (both ESCC and EAC) will serve as biomarkers to guide use of targeted inhibitors and that testing of therapeutics in genomically defined model systems will allow the identification of optimal agents and rational combinations of targeted agents. Three highly successful Core facilities are designed to provide esophageal cancer-specific services for the stimulation of collaborative research: Administrative/Biostatistics (Core A); Molecular Pathology and Imaging or MPIC (Core B); and Molecular BIology (Core C). The Program Project has the unequivocal support of the University of Pennsylvania Abramson Cancer Center and Perelman School of Medicine, the Dana Farber Cancer Institute (DFCI) and Fox Chase Cancer Center (each committed to robust new resources) and will continue to foster interdisciplinary research at Penn, DFCI and nationally that leads to a cooperative understanding of the molecular processes that form and regulate esophageal carcinogenesis with innovative opportunities in translational medicine. This highly productive and synergistic P01 involves integrated and innovative Projects, which are supported by robust and unique Core Facilities. Institutional support is truly outstanding. We seek to provide unique benefits in esophageal cancer to the biomedical research and clinical communities as well as to our patients.